A method for the treatment, prophylaxis, amelioration or prevention of disorders associated with abnormally high activity of steroidal estrogens, which includes administering to a human subject a composition comprising an isoflavone-containing extract of clover or chick peas, said extract comprising primarily biochanin, or a ratio of biochanin to one or more of the isoflavones from the group formononetin, daidzein and genistein in the range of from about 2:1 to about 5:1, optionally in association with one or more pharmaceutically acceptable carriers, excipients, auxiliaries and/or diluents is described. Also described are compositions and uses comprising the isoflavone containing extracts.

This is a National Stage application under 35 U.S.C. xc2xa7371 of PCT Application No. AU99/00222, filed Mar. 26, 1999, corresponding to Australian Patent Application No. PP 2607, filed Mar. 26, 1998.
This invention relates to methods and compositions for the treatment, prophylaxis, amelioration or prevention of disorders associated with abnormally high activity of steroidal estrogens, using a plant extract enriched for estrogenic isoflavones preferably comprising predominantly biochanin or a high ratio of biochanin to a mixture of other estrogenic isoflavones comprising formononetin, daidzein and genistein. The targeted conditions specifically include uterine fibroids, polycystic ovarian disease, ovarian cysts, mastalgia, cyclical acne, endometriosis and endometrial hyperplasia.
The aforementioned conditions usually are considered as a group because of a number of common characteristics. They occur almost exclusively in pre-menopausal women and therefore are thought to be associated with high blood levels of steroidal sex hormones, and they are associated with benign, hyperplastic and proliferative changes in the tissues of the is female reproductive tract (with the exception of cyclical acne).
The prominent role of steroidal estrogen in thee conditions is suggested by the observations firstly that these conditions and symptoms occur almost predominantly in pre-menopausal women and usually disappear with the onset of menopause, secondly, they often get worse during the mid-phase of the menstrual cycle when cyclical estrogen levels are highest, they usually are exacerbated by the use of steroidal estrogen therapy, and lastly they usually respond to therapies such as GnrH agonists, oral contraception, or oophorectomy, all of which have the effect of reducing steroidal estrogen production in the body.
Uterine fibroids are a particularly common problem with more than 30% of women developing fibroids by the time they reach menopause. Fibroids are benign adenomas originating in the uterine wall and composed of fibrous tissue. For some women, the fibroids can be small and essentially asymptomatic. For other women, the fibroids can be of such a size to cause symptoms such as severe menstrual bleeding and uterine cramping (with fibroids that disrupt the endometrium) or constipation and urinary frequency (with large, space-occupying fibroids that grow out into the pelvic cavity). Estrogen therapy is known to aggravate fibroids and the symptoms associated with fibroids [Grodstein et al. xe2x80x9cPostmenopausal hormone use and colecystectomy in a large prospective study.xe2x80x9d Obstetrics and Gynaecology: 1994: 83(1), 5-11; Akkad et al. xe2x80x9cAbnormal uterine bleeding on HRT: The importance of intrauterine structural abnormalities.xe2x80x9d Obstetrics and Gynaecology, 1995. 86(3): 330-334; Sener et al. xe2x80x9cThe effects of HRT on uterine fibroids in postmenopausal women.xe2x80x9d Fertility and Sterility, 1996. 65(2): 354-3571]. The usual treatment for fibroids is surgical removal (hysterectomy or hysterotomy).
Endometrial hyperplasia is thought to affect between 5-15% of pre-menopausal women. It involves an abnormal thickening of the endometrium that is not completely shed at the time of menstruation. The symptoms can include painful and heavy menstruation, and painful sexual intercourse. Treatment usually consists of surgery (curettage or hysterectomy).
Endometriosis affects about 5% of pre-menopausal women. This condition is due to the appearance of endometrium in the peritoneal cavity. Patches of endometrium can grow on the serosal surface of the ovaries, uterus, bladder, large intestine or the peritoneum. These patches respond to normal hormonal changes over the menstrual cycle in parallel to that of the endometrium the uterus and can bleed, swell and cause severe pelvic discomfort and pain. Standard therapy of endometriosis is surgical ablation of the abnormal tissue, although the recurrence rate is high, requiring ongoing surgical treatment [Namnoum et al. xe2x80x9cIncidence of symptom recurrence after hysterectomy for endometriosis.xe2x80x9d Fertility and Sterility, 1995. 64(5): 898-902]. Endometriosis also is aggravated by estrogen therapy [Goh et al. xe2x80x9cPostmenopausal endometrioma and HRTxe2x80x9d Australia New Zealand of Obstetrics and Gynaecology, 1992. 32(4): 384-385].
Ovarian cysts are thought to affect up to about 20% of pre-menopausal women. The pathology is that of multiple, incomplete follicles within the body of the ovary. A variant of this condition is known as polycystic ovarian disease which is characterised by excessive androgen production from the follicles stimulated by abnormally high insulin levels. Excess androgens are often converted to steroidal estrogen. The usual symptoms of polycystic ovarian disease are hirsutism and acne. The normal treatment for these conditions are GnrH agonists that function by down-regulating the release of gonadotrophins (FSH and LH) from the hypothalamus, thereby inhibiting and further ovulation.
Mastalgia is also known as cyclical mastalgia or fibrocystic breast disease. It is characterised by the retention of fluid in cysts within the fibrous tissue of the breast. It normally is associated with swelling, pain and tenderness, with symptoms usually worsening about the middle of the menstrual cycle when estradiol levels peak in the blood. No effective therapy for this condition is known.
Cyclical acne normally is restricted to post-adolescent women. It is associated with severe acne over the face and upper torso and normally the acne worsens on a cyclical basis in parallel with the menstrual cycle. The normal therapy for this condition is oral contraception in order to regulate ovulation and estrogen production.
In general, the management of these aforementioned conditions is unsatisfactory. Surgery is the most common method of treatment, and apart from the dramatic and intrusive nature of this approach, an inevitable outcome often is sterility as a result of removal of ovaries and/or uterus. The use of GnrH agonists also is not without adverse consequences as it invariably leads to premature menopause, with its attendant increased risks of osteoporosis and heart disease.
The underlying causes of or risk factors for the aforementioned conditions are unknown. Genetic risk factors are not reported, neither are lifestyle risk factors. There is no reliable epidemiological data reported that links the incidence of any one of these conditions or the group of conditions as a whole to specific communities or racial groups, or to lifestyle factors such as diet. However, it generally is recognised that the conditions or symptoms are associated with excess estrogen stimulation of tissues of the female reproductive tract and that it would be prudent to avoid any situation likely to aggravate estrogenic activity.
Plant estrogens including estrogenic isoflavones recently have come to medical attention because they mimic the effect/activity of steroidal estrogens and their biologically active analogues by binding to and activating estrogen receptors on animals (including human) cells. Plant isoflavones such as formononetin, biochanin, daidzein and genistein are known to be estrogenic in vitro, acting as agonists for the human estrogen receptor. Their ability to function as estrogens in the body is well understood and the epidemiological link between diets high in these estrogenic isoflavones and low incidences of certain estrogeneficiency states also is well documented. This has led to considerable interest in the use of dietary estrogens such as isoflavones to provide a supplementary estrogenic activity in menopausal women, providing relief from estrogen-deficiency symptoms including hot flushes, mood swings, osteoporosis, hypertension, and hypercholesterolaemia.
Given the current understanding about the estrogenic action of isoflavones, and the adverse consequences of estrogen therapy on the aforementioned pre-menopausal conditions and symptoms, estrogenic isoflavones would appear to be contra-indicated for subjects suffering from those conditions or symptoms. While the incidences of these conditions are adequately reported in women in Western countries where the diet is low in dietary isoflavones, there is no known data on the incidences in communities that typically ingest high levels of estrogenic isoflavones. It would be reasonable, however, to assume that it would particularly contra-indicated for pre-menopausal women at risk of the aforementioned conditions and symptoms to extensively consume foodstuffs such as clover that is the richest source of estrogenic isoflavones in nature. Therefore, the applicants were surprised to find that isoflavone-containing extracts of clover or chickpeas were particularly beneficial in the treatment of estrogen-sensitive conditions.
Clovers (Trifolium spp.) are one of the richest sources of estrogenic isoflavones in the plant kingdom, with some cultivars containing up to 5% of their dry weight as estrogenic isoflavones. The use of subterranean clovers in agriculture is associated with a condition in sheep known as xe2x80x98clover diseasexe2x80x99. This disease is due to excessive ingestion of estrogenic isoflavones resulting in hyperplastic changes in the lower reproductive tract. The linings of the uterus, cervix and vagina of sheep undergo dramatic proliferative changes and the ovaries show multiple cyst formation, all of which produces temporary and then permanent infertility. The pathology of these changes in sheep closely parallels that in humans with conditions such as endometaial hyperplasia. The likelood that estrogenic isoflavones might exacerbate such conditions in women, particularly in those women with little prior exposure to isoflavones, is therefore is a real concern.
Clovers such as red clover have enjoyed some therapeutic use by herbal practitioners over the centuries for various human ailments such as asthma and eczema and have not been noted as having any association with increased incidence of reproductive disorders. It should be noted that the traditional herbal use of red clover employs the flower and this part of the plant contains very little isoflavone. Also, red clover occurs in multiple cultivars and many cultivars have very low isoflavone levels. Thus it is not possible to ascribe any putative therapeutic benefit from herbal medicinal use to their isoflavone content, and nor is it possible to ascribe any apparent lack of adverse side effects to the safety of isoflavones.
In spite of this background, the applicant surprisingly has found that clover extracts preferably those enriched for certain estrogenic isoflavones may be used in the prevention and treatment of conditions of the female reproductive tract associated with excessive estrogen activity. Even more surprising is the finding that a particular ratio of different types of estrogenic isoflavones in the extract is primarily responsible for the demonstrated therapeutic effects. Preferably the extract comprises biochanin as the principal isoflavone. In the context of this invention, it has been found that the preferred ratio of biochanin to the other three main estrogenic isoflavones embraces the various naturally-occurring forms of isoflavones including their aglycone, glycoside, acetyl or malonyl forms.
In accordance with a first aspect of this invention there is provided a method for the treatment, prophylaxis, amelioration or prevention of disorders associated with an abnormally high activity of steroidal estrogen, which includes administering to a human subject a composition comprising an isoflavone containing extract of clover or chick pea, or an isoflavone extract of clover or chick pea comprising primarily biochanin or biochanin and any one or more of the isoflavones from the group formononetin, daidzein and genistein at a ratio from about 2:1 to about 5:1, optionally in association with one or more pharmaceutically acceptable carriers, excipients, auxiliaries and/or diluents.
Preferably the disorder is selected from uterine fibroids, polycystic ovarian disease, ovarian cysts, cyclical acne, mastalgia, endometriosis and endometrial hyperplasia.
By reference to an extract comprising xe2x80x9cprimarily biochaninxe2x80x9d is meant a biochanin content of at least 65% by weight isoflavone cot, such as 70 to 100%, more preferably 75 to 90% biochanin, the remainder of isoflavone content comprising essentially formononetin, daidzein and genistein.
The high ratio of biochanin to the other three estrogenic isoflavones in the range from about 2:1 to about 5:1 is responsible for the optimal unexpected therapeutic effects according to this invention. Outside of this range of ratios, the therapeutic benefits effectively are not observed, or if observed are considerably less effective. The ratio of biochanin to the other three isoflavones may, for example, be from about 7:3 to about 5:1.
In a further aspect of this invention there is provided a composition comprising an isoflavone-rich extract from clover or chick pea, said extract comprising a ratio of biochanin to formononetin, daidzein and genistein at a ratio from about 2:1 to about 5:1, optionally in association with one or more pharmaceutically acceptable carriers, excipients, auxiliaries, and/or diluents.
In a further aspect of the invention there is provided use of a composition comprising an isoflavone extract of clover or chick pea, said extract comprising primarily biochanin, or a ratio of biochanin to formonemn, daidzein and genistein at a ratio of from about 2:1 to about 5:1, optionally in association with one or more pharmaceutically acceptable carriers, excipients, auxiliaries, and/or filaments for the manufacture of a medicament for the treatment, prophylaxis, amelioration or prevention of disorders associated with an abnormally high activity of steroidal estrogen.
Scientific interest in isoflavones up until now has focused on daidzein and genistein. This is in part because of the belief that these two isoflavones are the most prominent in the human diet. But mainly it is because of the general belief that formononetin and biochanin are unlikely to have any biological significance in their own right. Formononetin and biochanin are mentholated versions of daidzein and genistein respectively and it is thought that humans have the capacity to convert formononetin to daidzein and biochanin to genistein. In sheep, the only animal species in which isoflavone metabolism has been extensively studied, this conversion is virtually 100% effective. Sheep consume predominantly formononetin and biochanin as a result of eating isoflavone-rich clovers, with virtually all formononetin being demethylated to daidzein and all biochanin being demethylated to genistein. Reports of analyses of blood or urine of humans ingesting diets rich in isoflavones has failed to demonstrate any formononetin and biochanin as being present, leading to the general assumption that the same situation applies in humans. That is, even if formononetin and biochanin are present in the diet, there is a general assumption that they are converted to daidzein and genistein and that it is these two isoflavones that hold the true source of biological significance to humans. The dominant use of soya as a source of dietary isoflavones by the health food and pharmaceutical industries is testament to this, with soya containing predominantly daidzein and genistein (95-99%) and only trace amounts of biochanin and formononetin.
The inventors were therefore very surprised to find that an extract of red clover or chick peas, preferably enriched for or comprising biochanin as the principal isoflavone, provided a therapeutic effect quite distinct from that seen with the same dose of isoflavones containing predominantly daidzein and genistein. This suggests that biochanin provides a distinctive and individualistic biological effect.
It has been recognized for some time that the four estrogenic isoflavones have an individual biological profile. That is, genistein is approximately ten fold more estrogenic than daidzein, and genistein has potent anti-cancer actions while daidzein has virtually none. The finding that biochanin might therefore also have a distinctive biological profile is not surprising, but that it should be able to maintain this distinction when its presence in the human body has not previously been demonstrated is surprising.
This finding was even more surprising given what generally is known about the action of isoflavones at the cellular level and the manner in which they function as estrogens. Compounds can exert an estrogenic effect in the body in one of two ways, either indirectly, by stimulating the brain to produce gonadotropins that in turn cause the body to make more estradiol, or directly, by attaching to and activating the human estrogen receptor (hER). The isoflavones are thought to act directly in the same way as the steroidal estrogen, estradiol, and some evidence exists to support that belief. Recent studies, however, point to isoflavones having an important difference to that of estradiol in the way they art as estrogens. Two distinct types of hER now have been identified, known as alpha-ER and beta-ER. Whereas estradiol binds with similar strengths to both ER types and appears to be able to stimulate both receptor types equally, the isoflavonoids are quite different. They show significantly greater agonism to the beta-ER than to the alpha-ER. The significance of this phenomenon lies in the fact that alpha-ER dominates on tissues of the female reproductive tract (vagina, endometrium, breast, ovary), while beta-ER dominates on most other tissues (brain, bone, endothelium etc.). The fact that isoflavones have weak affinity for alpha-ER is confirmed by clinical studies and epidemiological observations that diets rich in estrogenic isoflavones have little or no stimulatory effect on female reproductive tissue in post-menopausal women. But the experience with xe2x80x98Clover Diseasexe2x80x99 in sheep teaches us that this most likely is a dose-related effectxe2x80x94if sufficient isoflavones are ingested, then it is possible to achieve stimulation of the alpha-ER, producing proliferation of the reproductive tissues. Importantly, however, at normal dietary dosages, estrogenic isoflavones appear to have little or no impact on tissues expressing mainly alpha-ER.
Without wishing to be bound by any particular theory of action, there are multiple possible is mechanisms by which biochanin may be providing a therapeutic benefit in reducing the impact of steroidal estrogens on the reproductive tissues. One likely explanation is the way in which biochanin interacts with the alpha-ER, but this again is surprising given that there is no known difference in the way in which any of the four estrogenic isoflavones behave as ligands with this receptor.
It has been theorised that one of the biological effects of isoflavones is their ability to xe2x80x98competitively inhibitxe2x80x99 the action of steroidal estrogens such as estradiol. By this process, the isoflavonoid, being a weaker estrogen, once bound to the hER and occupying the receptor site, prevents the more estrogenic estradiol reaching the receptor. Isoflavones are weak estrogens, having an estrogenic potency between about 1:250 to 1:2,000 that of estradiol, and while they have considerably lower affinity for the hER compared to estradiol, the substantially greater numbers of isoflavones in the blood relative to estradiol means that a significant proportion of hER will be occupied by isoflavones. This theory holds that even though the isoflavonoid produces a weak estrogenic response, the fact that it has prevented a more potent response by estradiol means that the net effect has been one of a reduced estrogenic effect. This theory could be used to explain the ability of isoflavones to reduce the impact of estradiol on the female reproductive tissues during the pre-menopausal years when estradiol levels are at their highest.
Biochanin has about the same estrogenic potency as daidzein and there is some evidence that it has lower binding affinity for the hER compared to daidzein. Therefore even if competitive-inhibition is a contributing factor the clinical observation by the inventors, then it is even more surprising that an extract principally comprising biochanin should be more efficacious than an extract principally comprising daidzein and genistein.
Preferably the extract of clover is prepared by a water/water-miscible organic solvent extract of clover. The ratio of water to water-miscible organic solvent is generally in the range of 1:10 to 10:1 and may for example comprise equal proportions of water and solvent or from 1% to 30% (v/v) water-miscible organic solvent. Any water-miscible organic solvent or a mixture of such solvents may be used. The water-miscible organic solvent is preferably a C2-10, more preferably C1-4 water-miscible organic solvent (such as methanol, ethanol, propanol, propylene glycol, erythrite, butanol, butanediol, acetonitrile, ethyleneglycol, ethylacetate, glycidol, glycerol dihydroxyacetone or acetone). The extract in this regard is prepared by exposing the plant material to the water/water-miscible solvent mix. Optionally the mire may include an enzyme, which cleaves isoflavone glycosides to the aglucone form. The mixture may be vigorously agitated so as to form an emulsion. The temperature of the mix may range, for example, from an ambient temperature to boiling temperature. Exposure time may be between one hour to several weeks. One convenient extraction period is twenty-four hours at 90xc2x0 C. The extract is separated from undissolved plant material and the water-miscible organic solvent removed, such as by distillation, rotary evaporation or other standard procedures for solvent removal. The resultant extract containing water-soluble and non-water soluble components may be dried to give an isoflavone containing extract, which may be formulated with one or more pharmaceutically acceptable carriers, excipients and/or auxiliaries. The extract following distillation contains a small amount of oil which includes isoflavones in their aglucone form (referred to herein as isoflavones). This isoflavone-enriched oil, which may be dried, for example in the presence of silica, may be formulated with one or more carriers, excipients and/or auxiliaries to give an isoflavone containing extract. Alternatively, isoflavones may be further concentrated by addition to the oil of a non-water soluble organic solvent such as hexane, heptane or octane having high solubility for oils but low solubility for isoflavones. The oil readily partitions into the organic solvent, and an enriched isoflavone containing extract falls out of solution. The recovered extract may be dried, for example in an oven at 50xc2x0 C. to about 120xc2x0 C., and formulated with one or more pharmaceutically acceptable carriers, excipients and/or auxiliaries.
The clover (Trifolium spp.) may be red clover (T. pratense), subterranean clover (T. subterranean), white clover (T. repens), or any clover related species, or chick pea variety. Preferably the clover is red clover (T. pratense) or subterranean clover (T. subterranean).
The compositions according to the present invention may include one or more pharmaceutically acceptable carriers. Carriers are selected so as to be acceptable in the sense of being ingredients in the composition and must not be deleterious to the patient. The carriers may be solid or a liquid, or both, and may be formulated with the extract as a unit-dose, for example a tablet, which may contain from 0.5% to 80% by weight of extract or up to 100% by weight to extract. Compositions may be prepared by any of the well known techniques of pharmacy, for example admixing the extract, optionally including excipients, diluents (for example water) and auxiliaries as are well known in the pharmaceutical field.
The compositions according to the invention may include one or more agents, such as vitamins (for example, Vitamin A, Vitamin B group, Vitamin C, Vitamin D, Vitamin E and Vitamin K), and minerals (for example, magnesium, iron, zinc, calcium and manganese in the form of pharmaceutically acceptable salts).
The compositions of the invention include those suitable for oral, rectal, optical, buccal (for example sublingual), parental (for example subcutaneous, intramuscular, intradermal and intravenous) and transcermal administration. The most suitable route in any given case will depend on the nature and severity of the condition being treated and the state of the patient.
Compositions suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the extract; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such compositions may be prepared by any suitable method of pharmacy, which includes the step of bringing into association the active compound, and one or more suitable carriers (which may contain one or more accessory ingredients as noted above). In general the compositions of the invention are prepared by uniformly and intimately admixing the extract with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by comprising or moulding a powder or granules containing the extract, optionally with one or more accessory ingredients. Compressed tables may be prepared by compressing in a suitable machine, the extracts in the form of a powder or granules optionally mixed with a binder, lubricant, inert diluents, and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
Suitable carriers may be fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylceuflose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients may be flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredients.
Other orally administrable pharmaceutical compositions are dry-filled capsules made, for example, of gelatin, and soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise the extracts in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glicants, such as talc or magnesium stearate, and, where appropriate, stabilisers. In soft capsules, the extract is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.
Formulations suitable for buccal (sublingual) administration include lozenges comprising the extracts in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Compositions of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the extracts, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Suitable compositions include water soluble extracts and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions comprising viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, where appropriate, also stabilisers. As an example compositions may conveniently be prepared by admixing the extracts with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention may contain from 0.1% to 60% w/v of the extract and may, for example, be administered at a rate of 0.1 ml/minute/kg.
Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the extracts with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.
Compositions suitable for topical administration to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, and a combination of two or more thereof.
The extract is generally present at a concentration of from 0.1% to 30% weight/weight, for example from 0.5% to 10% weight/weight. The isoflavone ratio in the composition is preferably in the range of biochanin:formononetin from 2:1 to 8:1. Small or trace amounts of daidzein and biochanin may be present.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches may contain the extracts in an optionally buffered aqueous solution.
Compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the extracts. Such compositions may, for example, contain citrate or bis/tris buffer (pH 6) or ethanol/water, with for example 0.05% to 30% w/w extract.
Compositions may be prepared in a manner, and in a form/amount as is conventionally practised. See for example, Goodman and Gilllan, The Pharmalogical Basis of Therapeutics (7th Edition, 1985) and Remington""s Pharmaceutical Science (Mack Publishing Company, 10th Edition), both of which are incorporated herein by reference. Compositions ;nay contain, for example, from 0.1 mg to 2 g extract, such as 0.1 mg to 200 mg.
The extracts may be in the form of a powder, a slurry, in aqueous solution (for example containing a small amount of oil), particulate form, or dissolved in an organic solvent (such as methanol, ethanol, ethylacetate or dimethyl sulphoxide).
What constitutes an effective amount of the compositions of the present invention will depend upon a number of factors, such as specific mode of administration, the condition being treated, the condition of the patient and the judgment of the health care giver. Examples of dosages of extracts are about 0.1 mg to about 200 mg per day, such as in the order of 1.5 mg/kg (body weight)/day.
Preferably the extract comprises biochanin as the principal isoflavone. In the context of this invention, it has been found that the preferred ratio of biochanin to the other three main estrogenic isoflavones embraces the various naturally-occurring forms of isoflavones including their aglycone, glycoside, acetyl or malonyl forms.

Therapy of estrogen-associated disorders


The invention provides a thermosetting aqueous primer composition that includes a polyurethane polymer, an acrylic polymer, and a crosslinking component that is reactive with at least one of the polyurethane polymer and the acrylic polymer. The polyurethane polymer has a glass transition temperature of 0xc2x0 C. or less. The acrylic polymer has a glass transition temperature that is at least about 20xc2x0 C. higher than the glass transition temperature of polyurethane resin. The invention further provides a composite coating having as a primer layer a cured layer of the primer composition of the invention and having at least one topcoat layer.

The present invention relates to aqueous crosslinkable primer coating compositions and particularly such primer compositions that combine aqueous polyurethane dispersions and aqueous acrylic dispersions. The present invention further relates to composite coating finishes having one or more primer layers and one or more topcoat layers.
Coating finishes, particularly exterior coating finishes in the automotive industry, are generally applied in two or more distinct layers. One or more layers of primer coating composition may be applied to the unpainted substrate first, followed by one or more topcoat layers. Each of the layers supplies important properties toward the durability and appearance of the composite coating finish. The primer coating layers may serve a number of purposes. First, the primer coating may be applied in order to promote adhesion between the substrate and the coating. Secondly, the primer coating may be applied in order to improve physical properties of the coating system, such as corrosion resistance or impact strength, especially for improving resistance to gravel chipping. Third, the primer coating may be applied in order to improve the appearance of the coating by providing a smooth layer upon which the topcoat layers may be applied. The topcoat layer or layers contribute other properties, such as color, appearance, and light stabilization.
In the process of finishing the exterior of automobiles today, metal substrates are usually first coated with an electrocoat primer. While the electrocoat primer provides excellent surface adhesion and corrosion protection, it is often desirable to apply a second primer layer. The second primer layer provides additional properties not available from the electrocoat primer. Resistance to gravel chipping is one of the critical properties provided by the second primer layer. The second primer layer may also enhance the corrosion protection of the finish and provide a smoother surface than the electrocoat primer. The second primer also serves to provide a barrier layer between the electrocoat primer layer, which usually contains aromatic moieties and other materials that can cause yellowing on exposure to sunlight, and the topcoat.
Mitsuji et al, U.S. Pat. Nos. 5,281,655, 5,227,422, and 4,948,829, all of which are incorporated herein by reference, disclose automotive basecoat coating compositions containing polyurethane resin emulsion, a second resin emulsion than can be an acrylic resin, and a crosslinking agent. In Mitsuji ""829, the polyurethane resin is prepared by dispersing an isocyanate-functional prepolymer and having the water react with the isocyanate groups to chain-extend the prepolymer. The prepolymer is prepared using an aliphatic diisocyanate, a polyether or polyester diol, a low molecular weight polyol, and a dimethylolalkanoic acid. In Mitsuji ""655 and ""422, the polyurethane resin is prepared by reacting an aliphatic polyisocyanate, a high molecular weight polyol, a dimethylolalkanoic acid, and, optionally, a chain extender or terminator. Because the Mitsuji patents are directed to basecoat coatings, these patents provide no direction for preparing compositions that have the chip resistance and other properties required for primer coating layers.
Hatch et al., U.S. Pat. No. 5,817,735, incorporated herein by reference, discloses an aqueous primer composition for golf balls that includes a polyurethane dispersion and an acrylic dispersion. The primer has a very low content of volatile organic solvent, which is important for minimizing regulated emissions from the coating process. The Hatch patent, however, does not disclose a curable (thermosetting) composition. More importantly, the golf ball primers of the Hatch patent do not provide the properties, such as resistance to stone chipping and corrosion protection, that are required of an automotive primer.
It would be desirable, therefore, to have a primer composition that provides improved resistance to stone chipping and other properties that are important for an automotive primer, which additionally can be formulated with a very low content of volatile organic solvent.
The present invention provides a thermosetting primer composition that includes a polyurethane polymer, an acrylic polymer, and a crosslinking component that is reactive with at least one of the polyurethane polymer and the acrylic polymer. The polyurethane polymer has a glass transition temperature of 0xc2x0 C. or less. The acrylic polymer has a glass transition temperature that is at least about 20xc2x0 C. higher than the glass transition temperature of polyurethane resin. The polyurethane and acrylic polymers are preferably dispersed or emulsified in an aqueous medium. As used herein, xe2x80x9cemulsionxe2x80x9d or xe2x80x9cdispersionxe2x80x9d will each be used to refer both to dispersions and emulsions.
The invention further provides a composite coating having as a primer layer a cured layer of the primer composition of the invention and having at least one topcoat layer.
The polyurethane polymer of the invention has a glass transition temperature of about 0xc2x0 C. or less, preferably about xe2x88x9220xc2x0 C. or less, and more preferably about xe2x88x9230xc2x0 C. or less. The glass transition temperature of the polyurethane of the invention is in the range of from about xe2x88x9280xc2x0 C. to about 0xc2x0 C., more preferably from about xe2x88x9265xc2x0 C. to about xe2x88x9210xc2x0 C., still more preferably from about xe2x88x9265xc2x0 C. to about xe2x88x9230xc2x0 C., and even still more preferably from about xe2x88x9260xc2x0 C. to about xe2x88x9235xc2x0 C.
The weight average molecular weight of the polyurethane is preferrably from about 15,000 to about 60,000, more preferrably from about 15,000 to about 60,000, and even more preferably from about 20,000 to about 35,000.
Polyurethanes are prepared by reaction of at least one polyisocyanate and at least one polyol. The reactants used to prepare the polyurethane are selected and apportioned to provide the desired glass transition temperature. Suitable polyisocyanates include, without limitation, aliphatic linear and cyclic polyisocyanates, preferably having up to 18 carbon atoms, and substituted and unsubstituted aromatic polyisocyanates. Illustrative examples include, without limitation, ethylene diisocyanate, 1,2-diisocyanatopropane, 1,3-diisocyanatopropane, 1,4-butylene diisocyanate, lysine diisocyanate, 1,4-methylene bis(cyclohexyl isocyanate), isophorone diisocyanate, toluene diisocyanates (e.g., 2,4-toluene diisocyanate and 2,6-toluene diisocyanate) diphenylmethane 4,4xe2x80x2-diisocyanate, methylenebis-4,4xe2x80x2-isocyanatocyclohexane, 1,6-hexamethylene diisocyanate, p-phenylene diisocyanate, tetramethyl xylene diisocyanate, meta-xylene diisocyanate, 2,2,4-trimethyl-1,6-hexamethylene diisocyanate, 1,12-dodecamethylene diisocyanate, cyclohexane-1,3- and -1,4-diisocyanate, 1-isocyanato-2-isocyanatomethyl cyclopentane, and combinations of two or more of these. Biurets, allophonates, isocyanurates, carbodiimides, and other such modifications of these isocyanates can also be used as the polyisocyanates. In a preferred embodiment, the polyisocyanates include methylenebis-4,4xe2x80x2-isocyanatocyclohexane, 1,6-hexamethylene diisocyanate, 1,12-dodecamethylene diisocyanate, and combinations thereof. It is particularly preferred to use at least one xcex1,xcfx89-alkylene diisocyanate having four or more carbons, preferably 6 or more carbons, in the alkylene group. Combinations of two or more polyisocyanates in which one of the polyisocyanates is 1,6-hexamethylene diisocyanate are especially preferred.
The polyol or polyols used to prepare the polyurethane polymer can be selected from any of the polyols known to be useful in preparing polyurethanes, including, without limitation, 1,4-butanediol, 1,3-butanediol, 2,3-butanediol, 1,6-hexanediol, neopentyl glycol, 1,3-propanediol, 1,5-pentanediol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, diethylene glycol, triethylene glycol and tetraethylene glycol, propylene glycol, dipropylene glycol, glycerol, cyclohexanedimethanols, 2-methyl-2-ethyl-1,3-propanediol, 2-ethyl-1,3-hexanediol, thiodiglycol, 2,2,4-trimethyl-1,3-pentanediol, cyclohexanediols, trimethylolpropane, trimethylolethane, and glycerin; polyester polyols such as the reaction products of any of the foregoing alcohols and combinations thereof with one or more polycarboxylic acids selected from malonic acid, maleic acid, succinic acid, glutaric acid adipic acid, azelaic acid, anhydrides thereof, and combinations thereof; polyether polyols, such as polyethylene glycols and polypropylene glycols; and combinations of such polyols. Polyols having two hydroxyl groups are preferred. The polyurethane is preferably prepared using one or more polyester polyols. In a preferred embodiment, the polyester polyol is the reaction product of a mixture that comprises neopentyl glycol and adipic acid.
While it is possible to prepare a nonionic dispersion of the polyurethane, the polyurethane dispersion is preferably anionic. Acid-functional polyurethanes that can be salted to form anionic dispersions or emulsions may be synthesized by including a monomer having acid functionality, such as, without limitation, dialkylpropionic acids including dimethylolpropionic acid, and alkali metal salts of amino acids such as taurine, methyl taurine, 6-amino caproic acid, glycine, sulfanilic acid, diamino benzoic acid, ornithine, lysine and 1:1 adducts of sultones, such as propane sultone or butane sultone, with diamines, such as ethylene diamine, hydrazine, or 1,6-hexamethylene diamine. The hydroxyl groups react to form the urethane linkages while the acid group remains unreacted in the polyurethane polymerization.
Suitable polyurethane polymers can be prepared by any of the known methods. In one method for preparing polyurethane polymers, the polyisocyanate component is reacted with an excess of equivalents of the polyol component to form a hydroxyl-functional polyurethane polymer. Alternatively, an excess of equivalents of the polyisocyanate component can be reacted with the polyol component to form an isocyanate-functional prepolymer. The prepolymer can then be reacted further in different ways. First, the prepolymer can be reacted with a mono-functional alcohol or amine to provide a non-functional polyurethane polymer. Examples of mono-functional alcohols and amines that may be used include polyethylene oxide compounds having one terminal hydroxyl group, lower mono-functional alcohols having up to 12 carbon atoms, amino alcohols such as dimethylethanolamine, and secondary amines such as diethylamine and dimethylamine. Secondly, the prepolymer can be reacted with a polyfunctional polyol, polyamine, or amino alcohol compound to provide reactive hydrogen functionality. Examples of such polyfunctional compounds include, without limitation, the polyols already mentioned above, including triols such as trimethylolpropane; polyamines such as ethylenediamine, butylamine, and propylamine; and amino alcohols, such as diethanolamine. Finally, the prepolymer can be chain extended by the water during emulsification or dispersion of the prepolymer in the aqueous medium. The prepolymer is mixed with the water after or during neutralization.
The polyurethane may be polymerized without solvent. Solvent may be included, however, if necessary, when the polyurethane or prepolymer product is of a high viscosity. If solvent is used, the solvent may be removed, partially or completely, by distillation, preferably after the polyurethane is dispersed in the water. The polyurethane may have nonionic hydrophilic groups, such as polyethylene oxide groups, that serve to stabilize the dispersed polyurethane polymer. In a preferred embodiment, however, the polyurethane polymer is prepared with pendant acid groups as described above, and the acid groups are partially or fully salted with an alkali, such as sodium or potassium, or with a base, such as an amine, before or during dispersion of the polyurethane polymer or prepolymer in water.
The primer composition further includes an acrylic polymer. The acrylic polymer is prepared according to usual methods, such as by bulk or solution polymerization followed by dispersion in an aqueous medium or, preferably, by emulsion polymerization in an aqueous medium. The acrylic polymer is polymerized from a monomer mixture that preferably includes an active hydrogen-functional monomer and preferably includes an acid-functional monomer. Examples of active hydrogen-functional monomers include, without limitation, hydroxyl-functional monomers such as hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylates, and hydroxybutyl methacrylates; and carbamate- and urea-functional monomers or monomers with functional groups that are converted to carbamate or urea groups after polymerization such as, without limitation, those disclosed in U.S. Pat. No. 5,866,259, xe2x80x9cPrimer Coating Compositions Containing Carbamate-Functional Acrylic Polymers,xe2x80x9d the entire disclosure of which is incorporated herein by reference. Preferably, a sufficient amount of active hydrogen-functional monomer is included to produce an equivalent weight of 1000 or less grams per equivalent, more preferably 800 or less grams per equivalent, and even more preferably 600 or less grams per equivalent.
It is preferred that the acrylic polymer is dispersed as an anionic dispersion. Examples of suitable acid-functional monomers include, without limitation, xcex1, xcex2-ethylenically unsaturated monocarboxylic acids containing 3 to 5 carbon atoms, xcex1, xcex2-ethylenically unsaturated dicarboxylic acids containing 4 to 6 carbon atoms and the anhydrides and monoesters of these. Examples include, without limitation, acrylic acid, methacrylic acid, crotonic acid, maleic acid or maleic anhydride, itaconic acid or itaconic anhydride, and so on. A sufficient amount of acid-functional monomer is included to produce an acrylic polymer with an acid number of at least about 1, and preferably the acrylic polymer has an acid number of from about 1 to about 10.
In addition to the ethylenically unsaturated monomer having acid functionality or used to generate acid functionality in the finished polymer, one or more other ethylenically unsaturated monomers are employed as comonomers in forming the acrylic resins of the invention. Examples of such copolymerizable monomers include, without limitation, derivatives of xcex1, xcex2-ethylenically unsaturated monocarboxylic acids containing 3 to 5 carbon atoms, including esters, nitrites, or amides of those acids; diesters of xcex1, xcex2-ethylenically unsaturated dicarboxylic acids containing 4 to 6 carbon atoms; vinyl esters, vinyl ethers, vinyl ketones, vinyl amides, and aromatic or heterocyclic aliphatic vinyl compounds. Representative examples of acrylic and methacrylic acids, amides and aminoalkyl amides include, without limitation, such compounds as acrylamide, N-(1,1-dimethyl-3-oxobutyl)-acrylamide, N-alkoxy amides such as methylolamides; N-alkoxy acrylamides such as n-butoxy acrylamide; N-aminoalkyl acrylamides or methacrylamides such as aminomethylacrylamide, 1-aminoethyl-2-acrylamide, 1-aminopropyl-2-acrylamide, 1-aminopropyl-2-methacrylamide, N-1-(N-butylamino)propyl-(3)-acrylamide and 1-aminohexyl-(6)-acrylamide and 1-(N,N-dimethylamino)-ethyl-(2)-methacrylamide, 1-(N,N,-dimethylamino)-propyl-(3)-acrylamide and 1-(N, N-dimethylamino)-hexyl-(6)-methacrylamide.
Representative examples of esters of acrylic, methacrylic, and crotonic acids include, without limitation, those esters from reaction with saturated aliphatic and cycloaliphatic alcohols containing 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-ethylhexyl, lauryl, stearyl, cyclohexyl, trimethylcyclohexyl, tetrahydrofurfuryl, stearyl, sulfoethyl, and isobornyl acrylates, methacrylates, and crotonates; and polyalkylene glycol acrylates and methacrylates.
Representative examples of other ethylenically unsaturated polymerizable monomers include, without limitation, such compounds as fumaric, maleic, and itaconic anhydrides, monoesters, and diesters. Polyfunctional monomers may also be included to provide a partially crosslinked acrylic dispersion. Examples of polyfunctional compounds include, without limitation, ethylene glycol diacrylate, ethylene glycol dimethyacrylate, triethylene glycol diacrylate, tetraethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, divinylbenzene, trimethylolpropane triacrylate, and so on.
Representative examples of vinyl monomers that can be copolymerized include, without limitation, such compounds as vinyl acetate, vinyl propionate, vinyl ethers such as vinyl ethyl ether, vinyl and vinylidene halides, and vinyl ethyl ketone. Representative examples of aromatic or heterocyclic aliphatic vinyl compounds include, without limitation, such compounds as styrene, xcex1-methyl styrene, vinyl toluene, tert-butyl styrene, and 2-vinyl pyrrolidone.
After polymerization, the acid functionality is salted, preferably with an alkali or base, preferably an amine. Example of suitable salting materials include, without limitation, ammonia, monoethanolamine, ethylamine, dimethylamine, diethylamine, triethylamine, propylamine, dipropylamine, isopropylamine, diisopropylamine, triethanolamine, butylamine, dibutylamine, 2-ethylhexylamine, ethylenediamine propylenediamine, ethylethanolamine, dimethylethanolamine, diethylethanolamine, 2-amino-2-methylpropanol, and morpholine. Preferred salting materials include 2-amino-2-methylpropanol and dimethylethanolamine.
The acrylic polymers may be prepared as solutions in an organic solvent medium, preferably selected from water-soluble or water-miscible organic solvents, and then dispersed into water. After dispersion into water, the organic solvent can be distilled from the aqueous dispersion or emulsion.
In a preferred method, the acrylic polymer is provided by emulsion polymerization. Preferably, a nonionic or an anionic surfactant is used for the emulsion polymerization. Suitable surfactants include, without limitation, polyoxyethylenenonylphenyl ethers, polyoxyethylenealkylallyl ether sulfuric acid esters, amino and alkali salts of dodecylbenzenesulfonic acid such as the dimethylethanolamine salt of dodecylbenzenesulfonic acid and sodium dodecylbenzenesulfonic acid, and sodium dioctylsulfosuccinate.
The polymerization typically proceeds by free radical polymerization. The free radical source is typically supplied by a redox initiator or by an organic peroxide or azo compound. Useful initiators include, without limitation, ammonium peroxydisulfate, potassium peroxydisulfate, sodium metabisulfite, hydrogen peroxide, t-butyl hydroperoxide, dilauryl peroxide, t-butyl peroxybenzoate, 2,2xe2x80x2-azobis(isobutyronitrile), and redox initiators such as ammonium peroxydisulfate and sodium metabisulfite with ferrous ammonium sulfate. Optionally, a chain transfer agent may be used. Typical chain transfer agents include mercaptans such as octyl mercaptan, n- or tert-dodecyl mercaptan, thiosalicylic acid, mercaptoacetic acid, and mercaptoethanol; halogenated compounds; and dimeric alpha-methyl styrene.
Acrylic polymers prepared by emulsion polymerization can have weight average molecular weights of one million or more. The weight average molecular weight of the acrylic dispersion is preferably from about 5,000 to about 5,000,000, more preferably from about 7500 to about 500,000, and even more preferably from about 10,000 to about 50,000. If prepared by solution polymerization and then dispersed in water, the acrylic polymer will generally have a number average molecular weight of from about 5000 to about 60,000. The molecular weight can be determined by gel permeation chromatography using a polystyrene standard or other known methods. The theoretical glass transition temperature of the acrylic polymer can be adjusted according to methods well-known in the art through selection and apportionment of the comonomers. The acrylic polymer has a glass transition temperature that is at least about 20xc2x0 C. higher than the glass transition temperature of polyurethane resin. Preferably, the acrylic polymer has a glass transition temperature that is at least about 40xc2x0 C. higher, more preferably about 50xc2x0 C. higher, than the glass transition temperature of polyurethane resin. In a preferred embodiment, the theoretical Tg of the acrylic polymer is between about xe2x88x9230xc2x0 C. and 80xc2x0 C., more preferably between about xe2x88x9220xc2x0 C. and 40xc2x0 C.
The polyurethane polymer may be included in the primer in an amount of at least about 40% by weight, preferably at least about 50% by weight, based on the combined nonvolatile weights of the polyurethane polymer and the acrylic polymer. The polyurethane polymer may be included in the primer in an amount of up to about 98% by weight, preferably up to about 80% by weight, based on the combined nonvolatile weights of the polyurethane polymer and the acrylic polymer. It is preferred to include from about 50% by weight to about 75% by weight, and even more preferred to include from about 65% by weight to about 75% by weight, of the polyurethane polymer, based on the combined nonvolatile weights of the polyurethane polymer and the acrylic polymer.
The compositions of the present invention also include a crosslinker component. The crosslinker component includes one or more crosslinkers reactive with active hydrogen functionality. Examples of crosslinkers reactive S with active hydrogen functionality include, without limitation, materials having active methylol or methylalkoxy groups, including aminoplast resins or phenol/formaldehyde adducts; blocked polyisocyanate curing agents; tris(alkoxy carbonylamino) triazines (available from Cytec Industries under the tradename TACT); and combinations thereof. Suitable aminoplast resins are amine/aldehyde condensates, preferably at least partially etherified, and most preferably fully etherified. Melamine and urea are preferred amines, but other triazines, triazoles, diazines, guanidines, or guanamines may also be used to prepare the alkylated amine/aldehyde aminoplast resins crosslinking agents. The aminoplast resins are preferably amine/formaldehyde condensates, although other aldehydes, such as acetaldehyde, crotonaldehyde, and benzaldehyde, may be used. Non-limiting examples of preferred aminoplast resins include monomeric or polymeric melamine formaldehyde resins, including melamine resins that are partially or fully alkylated using alcohols that preferably have one to six, more preferably one to four, carbon atoms, such as hexamethoxy methylated melamine; urea-formaldehyde resins including methylol ureas and siloxy ureas such as butylated urea formaldehyde resin, alkylated benzoguanimines, guanyl ureas, guanidines, biguanidines, polyguanidines, and the like. Monomeric melamine formaldehyde resins are particularly preferred. The preferred alkylated melamine formaldehyde resins are water miscible or water soluble. Examples of blocked polyisocyanates include isocyanurates of toluene diisocyanate, isophorone diisocyanate, and hexamethylene diisocyanate blocked with a blocking agent such as an alcohol, an oxime, or a secondary amine such as pyrazole or substituted pyrazole.
The crosslinker component preferably is from about 2% by weight to about 30% by weight, and more preferably from about 5% by weight to about 20% by weight, and particularly preferably about 5% to about 15% by weight of the combined nonvolatile weights of the polyurethane, the acrylic polymer, and the crosslinking component.
The compositions may include one or more catalysts. The type of catalyst depends upon the particular crosslinker component composition utilized. Useful catalysts include, without limitation, blocked acid catalysts, such as para-toluene sulfonic acid, dodecylbenzene sulfonic acid, and dinonylnaphthylene disulfonic acid blocked with amines; phenyl acid phosphate, monobutyl maleate, and butyl phosphate, hydroxy phosphate ester; Lewis acids, zinc salts, and tin salts, including dibutyl tin dilaurate and dibutyl tin oxide.
The primer coating compositions according to the invention may further include pigments such as are commonly used in the art, including color pigments, corrosion inhibiting pigments, conductive pigments, and filler pigments. Illustrative examples of these are metal oxides, chromates, molybdates, phosphates, and silicates, carbon black, titanium dioxide, sulfates, and silicas.
Other conventional materials, such as dyes, flow control or rheology control agents, and so on may be added to the compositions.
The primer composition has a very low content of volatile of organic solvent. The polyurethane dispersion is preferably prepared as a solvent free or substantially solvent free dispersion. By xe2x80x9csubstantially solvent freexe2x80x9d it is meant that the dispersion has a volatile organic content of less than about 5% by weight of the primer composition. The acrylic dispersion is also preferably solvent free or substantially solvent free dispersion. The primer composition preferably has a volatile organic content of less than about 1.5, more preferably less than about 1.3, and even more preferably less than about 0.7. The volatile organic content of a coating composition is typically measured using ASTM D3960.
The coating compositions of the present invention can be applied over many different substrates, including wood, metals, glass, cloth, plastic, foam, metals, and elastomers. They are particularly preferred as primers on automotive articles, such as metal or plastic automotive bodies or elastomeric fascia. When the article is a metallic article, it is preferred to have a layer of electrocoat primer before application of the primer coating composition of the invention.
The composite coating of the invention has, as one layer, a primer coating layer that is obtained by reaction of the aqueous primer composition of the invention. The composite coating has a topcoat layer, which may include basecoat coating layer applied over the primer coating layer and an outer, clearcoat layer applied over the basecoat coating layer.
The primer coating composition of the invention is applied directly to the substrate or over one or more other layers of primer, such as the electrocoat primer. The applied primer coating composition is then cured to form a primer coating layer. The electrocoat primer or other first layer of primer may be cured at the same time as the primer coating layer of the invention in a process known as xe2x80x9cwet-on-wetxe2x80x9d coating. The primer coating layer formed from the primer coating composition of the invention is the outermost primer layer of the composite coating.
A topcoat composition is applied over the primer coating layer and cured to form a topcoat layer. The substrate at that point is then covered with a composite coating that has at least one layer of primer coating derived from the inventive compositions and at least one layer of topcoat. In a preferred embodiment, the coating composition of the present invention is overcoated with a topcoat applied as a color-plus-clear (basecoat-clearcoat) topcoat. In a basecoat-clearcoat topcoat, an underlayer of a pigmented coating, the basecoat, is covered with an outer layer of a transparent coating, the clearcoat. Basecoat-clearcoat topcoats provide an attractive smooth and glossy finish and generally improved performance.
Crosslinking compositions are preferred as the topcoat layer or layers. Coatings of this type are well-known in the art and include waterborne compositions as well as solventborne compositions. For example, the topcoat may be a clearcoat according to U.S. Pat. No. 5,474,811, applied wet-on-wet over a layer of a basecoat composition. Polymers known in the art to be useful in basecoat and clearcoat compositions include, without limitation, acrylics, vinyl, polyurethanes, polycarbonates, polyesters, alkyds, and polysiloxanes. Acrylics and polyurethanes are preferred. Thermoset basecoat and clearcoat compositions are also preferred, and, to that end, preferred polymers comprise one or more kinds of crosslinkable functional groups, such as carbamate, hydroxy, isocyanate, amine, epoxy, acrylate, vinyl, silane, acetoacetate, and so on. The polymer may be self-crosslinking, or, preferably, the composition may include a crosslinking agent such as a polyisocyanate or an aminoplast resin of the kind described above. In one embodiment, waterborne basecoat compositions and/or clearcoat compositions having low volatile organic content are used. The waterborne basecoat and waterborne clearcoat compositions each preferably has a volatile organic content of less than about 1.5, more preferably less than about 1.3, and even more preferably less than about 0.7.
Each layer of the composite coatings of the invention can be applied to an article to be coated according to any of a number of techniques well-known in the art. These include, for example, spray coating, dip coating, roll coating, curtain coating, and the like. If an initial electrocoat primer layer is applied to a metallic substrate, the electrocoat primer is applied by electrodeposition. For automotive applications, the primer coating composition of the invention and the topcoat layer or layers are preferably applied by spray coating, particularly electrostatic spray methods. Coating layers of one mil or more are usually applied in two or more coats, separated by a time sufficient to allow some of the solvent or aqueous medium to evaporate, or xe2x80x9cflash,xe2x80x9d from the applied layer. The flash may be at ambient or elevated temperatures, for example, the flash may use radiant heat. The coats as applied can be from 0.5 mil up to 3 mils dry, and a sufficient number of coats are applied to yield the desired final coating thickness.
The outermost primer layer, which is formed by reacting the primer compositions of the invention, may be cured by reaction of curing component with at least one the polyurethane resin or the acrylic resin. before the topcoat is applied. The cured primer layer may be from about 0.5 mil to about 2 mils thick, preferably from about 0.8 mils to about 1.2 mils thick.
Color-plus-clear topcoats are usually applied wet-on-wet. The compositions are applied in coats separated by a flash, as described above, with a flash also between the last coat of the color composition and the first coat the clear. The two coating layers are then cured simultaneously. Preferably, the cured basecoat layer is 0.5 to 1.5 mils thick, and the cured clear coat layer is 1 to 3 mils, more preferably 1.6 to 2.2 mils, thick.
Alternatively the primer layer of the invention and the topcoat can be applied xe2x80x9cwet-on-wet.xe2x80x9d For example, the primer composition of the invention can be applied, then the applied layer flashed; then the topcoat can be applied and flashed; then the primer and the topcoat can be cured at the same time. Again, the topcoat can include a basecoat layer and a clearcoat layer applied wet-on-wet.
The coating compositions described are preferably cured with heat. Curing temperatures are preferably from about 70xc2x0 C. to about 180xc2x0 C., and particularly preferably from about 170xc2x0 F. to about 200xc2x0 F. for a composition including an unblocked acid catalyst, or from about 240xc2x0 F. to about 275xc2x0 F. for a composition including a blocked acid catalyst. Typical curing times at these temperatures range from 15 to 60 minutes, and preferably the temperature is chosen to allow a cure time of from about 15 to about 30 minutes. In a preferred embodiment, the coated article is an automotive body or part.
The primer layer of the invention provides improved chip resistance as compared to previously known primers, while retaining the desirable properties of sandability and corrosion resistance. Further, the primer composition of the invention can be formulated to have low volatile organic content and even no volatile organic content.

Waterborne primer with improved chip resistance


A method is provided for reducing the vapour pressure (RVP) of a gasoline/alcohol mixture which comprises adding a surfactant composition comprising an alkanolamide, an alkoxylated alcohol and an alkoxylated fatty acid to a gasoline/alcohol mixture.

The invention relates to a novel method of reducing the vapour pressure of fuels and to the new use of compositions.
It is well known that liquid fuels when burned in an internal combustion engine can give rise to pollution and other undesired side effects. Furthermore, the relatively high vapour pressure of most liquid hydrocarbon fuels is known to give rise to environmental and safety problems upon storage and transportation. Numerous proposals have been advanced to reduce these side effects and enhance efficiency, eg miles per gallon. It has been realised that surfactants can play a useful role in this context but so far as we are aware none has satisfied the modern commercial criteria. It is one object of this invention to meet the need.
According to the US Environmental Protection Agency (EPA), volatile organic compound (VOC) emissions from gasoline are, as ozone precursors, a major contributor to the nation""s serious ground level ozone problem, which harms human health and the public welfare. In addition to automotive emissions, gasoline evaporation occurs during refining, during commercial handling, transportation, and storage, and during refuelling. Because gasoline evaporation is a significant environmental problem, work was initiated at the National Alternative Fuels Laboratory (NAFL) of the University of North Dakota Energy and Environmental Research Center (EERC) to investigate evaporation rates of various gasolines and gasoline-oxygenate blends and the composition of their evaporative emissions. One aspect of the work, which was funded by the US Department of Agriculture (USDA), was to compare evaporation rates and compositions of E10 evaporative emissions with those of nonethanol-blended base fuels.
Widespread commercial use of E10 fuels was originally promoted as a means to reduce gasoline consumption during the oil embargo of 1973. Current interest in ethanol as a transportation fuel involves its use as an oxygenate to reduce carbon monoxide (CO) combustion emissions. Also, its octane-boosting quality makes it useful as a replacement for octane-supplying aromatics that are slated for removal from reformulated gasolines to be sold in ozone non-attainment areas. Despite its desirable qualities as a fuel and the fact that it is renewable, ethanol has serious competition. Ethanol supporters are locked in a long-term debate with supporters of the other major commercially available gasoline oxygenate, methyl tertiary-butyl ether (MTBE), over which oxygenate is best for the environment.
A major point of contention in the debate is the approximate one-pound per square inch (psi) increase in RVP that occurs upon addition of ethanol to base fuel at a concentration of 10 vol %. However, while RVP is a useful indicator of a fuel""s volatility, it is less useful as an indicator of how atmospheric interaction of vapour from the fuel (generated via evaporation or displacement during tank filling) may affect the environment in terms of ground level ozone production. Because gasolines are complex mixtures of over 200 components, the overall ozone-producing potential of a particular gasoline""s vapour will depend not only on how much vapour is emitted, but also on the ozone-producing potential and concentration of each vapour component.
Surfactants have long had utility as additives which can affect the performance of fuels such as gasoline and diesel. British Patent No 2217229 describes a solubilising compound as a fuel additive. In particular there is described a composition comprising;
48 parts by volume of an alcohol ethoxylate;
3-8 parts by volume of lauric diethanolamide;
3-8 parts by volume of oleic diethanolamide; and
1.5-4 parts by volume of a polyglycol ether such as ethoxylated oleic acid.
Such compositions are useful as fuel additives and enable the solubilisation of water in fuels thus reducing its potential corrosive effect. However, the compositions are disadvantageous in that, inter alia, they require a high additive to fuel ratio. Furthermore, they do not address the problems of emissions of gases such as CO, CO2 and NOX, nor do they address the problems of evaporative loss due to the high vapour pressure of the fuel composition.
International Patent Application No WO 98/17745 describes an alternative formulation which comprises,
25% w/w of a diethanolamide,
50% w/w of an ethoxylated alcohol, and
25% w/w of a fourteen carbon chain fatty acid with seven ethoxylate groups.
WO ""745 especially describes fuel compositions comprising, inter alia, an additive made up of a fatty acid diethanolamide, an alcohol ethoxylate and an ethoxylate of a fatty acid, the degree of ethoxylation being selected so that a long term stable fuel composition is formed and, in particular, wherein, by carefully selecting the degree of ethoxylation, a balanced blend can be produced, such that the molecular weight ratios of each of the three components are substantially equivalent, for example, the molecular weight ratios are 1:1:1.
Whilst such additives provide significant reductions in emissions and are useable at low concentrations, there is still a need for a fuel composition which is capable of reducing emissions whilst maintaining performance levels.
It is known that to meet some legislation requirements fuels must have a low Reid Vapour Pressure value (RVP), e.g. under California State law, the RVP must be below 7 psi (0.48 atmospheres).
Some modern day gasoline contains a small percentage of the condensate from natural gas pipelines. Gasoline is made up from a range of hydrocarbons, which is determined by the refining and blending processes. They may also contain minor amounts of comparatively volatile contaminants picked up during transportation, for example, through pipe lines which have been previously used for transportation of natural gases. Pentanes are a range of C5 hydrocarbons that are typically left in the crude oil cut after the gas condensates are removed. Natural gas (methane) is extracted first from the oil field, ethane is increasingly also extracted at the well for petrochemical production of ethylene, while LPG, a mixture of C3 and C4 hydrocarbons, is liquefied under moderate pressure for use as a gas fuel. Pentane is usually the first cut off the Crude Distillation Unit at the refinery and the disposal of pentane creates a problem for the petroleum industry. Pentane has little value as a petrochemical feedstock, and blending it into the gasoline pool has the undesirable effect of raising the RVP. The aforementioned contaminants, as well as low boiling fractions arising from the refining and blending processes, all have the undesirable effect of increasing the vapour pressure of the gasoline. This undesirable effect will be further exacerbated if the fuel is blended with certain volatile oxygenating agents such as ethanol. Thus the condensate is a light fraction which is primarily pentanes although other hydrocarbons may be present. The condensate adversely affects the RVP, especially when the gasoline contains an alcohol such as ethanol.
It is known that when gasoline and an alcohol are mixed, the resultant mixture has an increased vapour pressure. We have now surprisingly found that by adding certain surfactant compositions to a gasoline and alcohol mixture a reduction in vapour pressure (RVP) can be achieved.
Thus, according to the invention we provide a method of reducing the vapour pressure of a gasoline/alcohol mixture which comprises adding a surfactant composition comprising an alkanolamide, an alkoxylated alcohol and an alkoxylated fatty acid, or an ester thereof characterised in that the RVP is less than 7 psi (0.48 atmospheres) to a gasoline/alcohol mixture.
By the term vapour pressure we mean the Reid Vapour Pressure (RVP). Thus the method of the invention preferably reduces the RVP of the gasoline mixture to less than 7 psi (0.48 atmospheres) and especially between 6(0.41 atmospheres) and 7 psi (0.48 atmospheres).
For the purposes of this invention the RVP is measured using the test method of ASTM D5191. Thus the vapour pressure is given at 37.8xc2x0 C.
It is a novel aspect of the invention to use the aforementioned surfactant composition in the reduction of RVP.
According to a further aspect of the invention we provide the use of an additive composition as hereinbefore described in the manufacture of a fuel composition having an RVP of less than 7 psi (0.48 atmospheres).
The alkanolamide is preferably an ethanolamide and more preferably a diethanolamide. Especially preferred are the diethanolamides and particularly the super diethanolamides. By the term super diethanolamide we mean a diethanolamide in which the nitrogen is substituted by an alkyl substituent e.g. alkyl C5 to C20, preferably C8 to C16, more preferably C10 to C15. The most preferred diethanolamide has a C12 alkyl substituent i.e. lauryl diethanolamide. Where the amides are derived from natural products this moiety will have an even number of carbon atoms, e.g. 12 for the lauryl derivative. Note, the alkyl part of this group is the R group which will be an odd number.
There are three commercial routes to alkanolamides;
Acid+alkanolamine=alkanolamide+water
Plant or animal oil (triglyceride)+alkanolamine=alkanolamide+glycerol
Methyl ester+alkanolamine=alkanolamide+methanol.
These are listed in order of increasing product quality. The route via the acid often uses an excess of alkanolamine to produce a product higher in amide than is obtainable from the acid if a stoichiometric ratio is used; these products are sometimes referred to as super amides.
The alkoxylated alcohol is preferably an ethoxylated alcohol. It is essential that the ethoxylated alcohol is an oil soluble alcohol. Therefore, alkanols are preferred and these may be primary, secondary or tertiary alkanols and especially primary alkanols. As the oil solubility of the alcohol may vary with the carbon chain length of the ethoxylated alkanol, the alkanol is preferably a C5 to C22 alkanol, more preferably C5 to C15 alkanol. The ethoxylated alcohol may comprise a mixture of alkanols. However, it is preferred that in such mixtures one alkanol will predominate. Thus, the most preferred alkanol is predominantly a C9 to C11 alkanol. In addition the degree of ethoxylation of the alcohol may be varied and the oil solubility will, generally, decrease with the increase in the degree of ethoxylation. It is preferred that the ethoxylate to alcohol ratio is greater than 2. More preferably, the ethoxylate to alcohol ratio is from between 1 and 10, preferably between 1 and 5, more preferably between 1 and 3 and especially between 2 and 3. A commercially available ethoxylated alcohol is especially preferred in which the ethoxylate to alcohol ratio is 2.75. Such an alcohol ethoxylate is available as NEODOL 91/2.5.
The fatty acid ethoxylate may comprise any conventionally known fatty acid ethoxylate. Thus the fatty acid ethoxylate may be derived from a fatty acid having from 8 to 20 carbon atoms, preferably from 10 to 18 and most preferably 14 carbon atoms (myristic acid).
The degree of ethoxylation is chosen to optimise performance in the blend with the other two selected surfactants and may be from 1 to 20, but more preferably from 5 to 12. A suitable product within this range would be, for example that derived from the addition of 7 molecules of ethylene oxide too 1 mole of myristic acid.
The values will depend on the length of the hydrophilic chain, typically an ethoxylate chain. The length of the chain will increase the extent of solubilisation because of a greater ability to solubilise.
As with the compositions described in WO98/17745, a blend of surfactants is preferred, preferably by selecting one appropriate to the fuel, say 10 to 18 for hydrocarbon fuel, most preferably 13. In the case of an alcohol the HLB value of the surfactant is between 3 and 7, most preferably about 4. But the addition of surfactants normally create ratios of 1:1 or high volume emulsions or 5:1 ratios when the solubalisation is required at 1:100.
The invention has the ability to unify the HLB requirements of any liquid fuel which in turn allows for one dose to be used in any fuel from C5 carbon chains up. The benefit being the amount of treatment directly related to the co-solvency ability.
Preferably the ethoxylate of the fatty acid makes up about 25% by volume of the additive and further preferably the alcohol ethoxylate comprises 50% by volume of the additive.
The surfactant additive may be added to a hydrocarbon fuel, eg diesel, petrol or alcohol, such as ethanol which may or may not be contaminated with water.
The fuel composition comprising a fuel and a fuel additive wherein the additive to fuel ratio is 0.5-1:1200.
The alcohol to hydrocarbon fuel ratio is from 1:8 to 1:9. Water may be present, e.g. as condensate, or added separately, in water: alcohol: fuel ratio of 0:1:8 to 0.5:;1:9 and preferably from 0.25:1:8 to 0.25:1:9.
The additive may be present in an additive to fuel/alcohol ratio of about 0.5-1:1000. Preferably the additive to fuel ratio is about 1:1000, most preferably about 1:1200. In this context the fuel is the hydrocarbon fuel and alcohol mixture.